The cytotoxicity profile of the topoisomerase I (top 1) inhibitors camptothecin (3) and indenoisoquinoline 2 (see FIG. 3) has been described by Kohlhagen et al. in Mol. Pharmacol. 54:50-58 (1998); Pommier et al. in Biochem. Biophys. Acta, 1400:83-105 (1998); and Pommier in Opinion in Oncologic, Endocrine & Metabolic Investigational Drugs, 1:168-169 (1999), the disclosures of which are incorporated herein by reference. The synthesis of indenoisoquinoline 2 is accomplished by treatment of the cis-substituted isoquinolone 1 (FIG. 3) with thionyl chloride, as described by Cushman & Cheng in J. Org. Chem. 43:3781-83 (1978), the disclosure of which is incorporated herein by reference. Both camptothecin (3) and indenoisoquinoline 2 were also shown to be inhibitors of DNA religation reactions occuring after DNA cleavage by the enzyme, i.e., top1-catalyzed single strand breakage. Both camptothecin (3) and indenoisoquinoline 2 might be better classified as a top1 poisons than a top1 suppressors because camptothecin (3) and indenoisoquinoline 2 showed the ability to stabilize the cleavable complexes. However, the DNA single-strand breaks induced by indenoisoquinoline 2 were more stable than those induced by camptothecin (3). Furthermore, the cleavage site specificity of 2 was different from that of camptothecin (3).
Although several camptothecin (3) derivatives such as irinotecan and topotecan are clinically useful anticancer agents, they are unstable due to opening of the lactone ring present on each of these compounds; thus, subsequent rapid reversibility of the cleavage complexes is observed after drug removal. Consequently, there is a present need for additional therapeutic agents that inhibit top1 like the camptothecins, but that induce novel DNA cleavage patterns, have modified toxicity profiles and extended durations of action, and display different antitumor spectra relative to the camptothecins themselves. A number of analogs of the indenoisoquinoline 2 have been synthesized, as described by Strumberg et al. in J. Med. Chem. 42:446-457 (1999); Cushman et al. in J. Med. Chem. 43:3688-3698 (2000); and Jayaraman et al. in J. Med. Chem. 45:242-249 (2002).